In this request to extend the MERIT application for an additional five years, we have focused on the major developments in both progress and plans for the future research. The last four years has seen very exciting developments in our conception of the pathogenesis of Alzheimer's disease, and the development of a novel, testable hypothesis. This hypothesis links the development of tau pathology, the activationof components of the cell cycle and neuronal degeneration, which may be due to the activation of the abl family of protein tyrosine kinases. With the support of this MERIT extension we plan direct testing of this hypothesis. If the hypothesis is supported by the work proposed, there will be direct and simple paths to new therapeutics for Alzheimer's disease. Although this project could be considered high risk research, the rewards will be considerable if it is successful. In the application, the progress leading to the development of the new hypothesis is reviewed, and the research plan is designed to rigorously assess it's validity through the characterization of new transgenic mice. Parallel studies in human brain and cell culture, supported by other finds, will provide additional relevant information. The specific aims of this application are: 1. To establish whether c-abl or Arg activation occurs in the hTau mouse prior to cell cycle activation and neuronal death. 2. To construct and analyze transgenic mice with inducible, neuron-specific expressionof constitutively active c-abl. Similar mice with inducible, neuron-specific expression of constitutively active Arg will also be made. The prediction is that expression of the constitutively active abl kinases will result in cell cycle activation, tau (and perhaps amyloid) pathology, and cell death. 3. Assuming that neuron-specific expression of constitutively active c-abl (and/or Arg) does cause neuronal pathology, mice with inducible, neuron-specific expression of kinase-defective c-abl or Arg will also be made. 4. To examine the role of tau in cell cycle mediated cell death. The c-abl and Arg mice made under specific aim 2 will be crossed into the tau knockout, and into mice with the human tau gene, to examine the influence of tau on the expressionof pathology.